Physicochemical and Biopharmaceutical Controllability of New Self-Assembled Fatty Acid Conjugated Leuprolide for the Enhanced Anticancer Activity.
LEU–fatty acid conjugate
enhanced permeability
fattigation
fatty acid chain length
improved anticancer activity
leuprolide
self-assembled nanoparticles
Journal
International journal of nanomedicine
ISSN: 1178-2013
Titre abrégé: Int J Nanomedicine
Pays: New Zealand
ID NLM: 101263847
Informations de publication
Date de publication:
2023
2023
Historique:
received:
11
12
2022
accepted:
11
04
2023
medline:
15
5
2023
pubmed:
12
5
2023
entrez:
11
5
2023
Statut:
epublish
Résumé
Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity. To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs). LEU-fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3. Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days. The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.
Sections du résumé
Background
UNASSIGNED
Leuprolide (LEU), a synthetic nonapeptide analog of naturally occurring gonadotropin-releasing hormone (GnRH), could exert a direct inhibitory activity on the proliferation of prostate cancer cells. However, the short half-life in blood and the biopharmaceutical problem of LEU limit this anticancer activity.
Purpose
UNASSIGNED
To improve its druggability for improving anticancer activity, the amine-group targeted LEU was conjugated with different chain lengths of saturated fatty acids (FAs).
Methods
UNASSIGNED
LEU-fatty acid conjugates (LFCs) were synthesized by exploiting N-hydroxysuccinimidyl (NHS) conjugation chemistry. The physicochemical properties and the self-assembled behaviors of the conjugates were extensively investigated. The in vitro anticancer activity of three LFCs was extensively studied in both 2D monolayer and 3D spheroid culture models of a prostate cancer cell line, PC3.
Results
UNASSIGNED
Three LFCs could be readily self-assembled into nanoparticles (LFNs) with a small size of around 100 nm, positive charges, and exhibited greater permeability rates compared to the same concentration of LEU, excluding LSN. The chain length of FA in conjugate was positively related to the selectivity index between cancer cells and non-cancerous cell lines. All LFCs showed a superior direct antiproliferative effect on cancer cells in the following order: LSC (98.9%) > LPC (86.7%) > LLC (75.0%) > LEU (8.9%) after repeat daily of the same dose strength of LEU for 4 days. In addition, the 3D spheroid model study indicates that all LFCs with a one-time treatment performed a long-acting inhibitory effect on tumor growth as compared to LEU after 7 days.
Conclusion
UNASSIGNED
The conjugation of LEU with different chain lengths of FAs could provide a novel strategy to improve peptide stability and exert an additional superior direct inhibitory effect for the treatment of several hormone-responsive tumor systems using therapeutic peptides.
Identifiants
pubmed: 37168738
doi: 10.2147/IJN.S401048
pii: 401048
pmc: PMC10166105
doi:
Substances chimiques
Leuprolide
EFY6W0M8TG
Fatty Acids
0
Biological Products
0
Gonadotropin-Releasing Hormone
33515-09-2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2325-2344Informations de copyright
© 2023 Ngo et al.
Déclaration de conflit d'intérêts
The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
Références
Int J Nanomedicine. 2022 May 17;17:2243-2260
pubmed: 35615542
Gynecol Oncol. 1994 Jul;54(1):80-6
pubmed: 8020844
Int J Oncol. 2007 Jan;30(1):261-71
pubmed: 17143537
Biopolymers. 2011;96(3):260-72
pubmed: 20632397
Cold Spring Harb Perspect Med. 2018 Jun 1;8(6):
pubmed: 29101113
ACS Med Chem Lett. 2014 Oct 27;5(12):1290-5
pubmed: 25516786
Q J Nucl Med Mol Imaging. 2015 Dec;59(4):374-80
pubmed: 26222275
Adv Exp Med Biol. 2017;1030:185-227
pubmed: 29081055
Bioorg Med Chem. 2020 Feb 15;28(4):115306
pubmed: 31926774
Oncol Lett. 2021 Oct;22(4):689
pubmed: 34457044
Macromol Biosci. 2020 Sep;20(9):e2000050
pubmed: 32633851
Eur J Pharm Biopharm. 2019 Sep;142:315-321
pubmed: 31299277
Expert Opin Investig Drugs. 2007 Nov;16(11):1851-63
pubmed: 17970643
CA Cancer J Clin. 2001 Jan-Feb;51(1):15-36
pubmed: 11577478
Sci Transl Med. 2019 Feb 6;11(478):
pubmed: 30728288
J Control Release. 2020 Aug 10;324:55-68
pubmed: 32380202
J Biomed Nanotechnol. 2013 Aug;9(8):1416-31
pubmed: 23926810
Oncol Rep. 2017 Oct;38(4):2105-2115
pubmed: 28765876
Eur J Pharm Biopharm. 2015 Jan;89:365-73
pubmed: 25536111
J Pharm Sci. 2001 Feb;90(2):194-201
pubmed: 11169536
Int J Pharm. 2019 Jun 10;564:124-135
pubmed: 30991133
Pediatrics. 2002 Feb;109(2):E30
pubmed: 11826240
ACS Omega. 2020 Aug 20;5(34):21513-21523
pubmed: 32905373
J Vis Exp. 2015 Nov 20;(105):
pubmed: 26649463
Colloids Surf B Biointerfaces. 2018 Oct 1;170:179-186
pubmed: 29906703
J Pharmacol Exp Ther. 2015 Feb;352(2):380-94
pubmed: 25491146
Int J Mol Sci. 2021 Oct 02;22(19):
pubmed: 34639049
Eur J Pharm Biopharm. 2020 Sep;154:8-17
pubmed: 32634569
Talanta. 2016;146:369-74
pubmed: 26695277
Prostate. 1995 Apr;26(4):179-88
pubmed: 7716082
J Dairy Sci. 2022 Apr;105(4):3508-3517
pubmed: 35094866
JAMA. 2017 Jun 27;317(24):2532-2542
pubmed: 28655021
Mol Carcinog. 2013 Mar;52(3):167-82
pubmed: 22162252
Clin Adv Hematol Oncol. 2018 Apr;16(4):289-295
pubmed: 29742084
Eur J Pharm Biopharm. 2020 Jul;152:257-269
pubmed: 32422167
Eur J Med Chem. 2022 Sep 5;239:114557
pubmed: 35759906
J Pers Med. 2021 Aug 06;11(8):
pubmed: 34442415
Cancer Res. 1994 Aug 1;54(15):4091-5
pubmed: 8033142
Bioconjug Chem. 2018 Jul 18;29(7):2296-2308
pubmed: 29856926
Cancers (Basel). 2022 Jan 14;14(2):
pubmed: 35053570
Mater Sci Eng C Mater Biol Appl. 2017 Jan 1;70(Pt 1):889-896
pubmed: 27770966